Combination chemotherapy of drug-resistant Trypanosoma brucei rhodesiense infections in mice using DL-alpha-difluoromethylornithine and standard trypanocides (original) (raw)
Related papers
Introduction: Studies using clones in the laboratory show variations in pathogenicity and drug sensitivity compared to their respective natural isolates for various trypanosome species. This suggests that within isolates there exist sub-populations due to change overtime. This study characterized Trypanosoma brucei rhodesiense isolated from patients in two different sleeping sickness foci, (Busoga and Busia) and evaluated the change in drug sensitivity and pathogenicity with time of isolation. Methods: In the study, various Trypanosoma brucei rhodesiense clones and their respective isolates were tested for pathogenicity and sensitivity to drugs (Suramin and Mel B) in Swiss white mice. The clinical, pathological and sensitivity parameters were determined. Results: When compared with the specific isolates, clones had lower mean pre-patent periods and lower mean post infection survival times. Furthermore, when compared with the controls, packed cell volume (PCV) changes for all the clones were significantly different (p<0.05) but this was not the case for the isolates. Conclusion: The study concluded that the clones were more pathogenic than their isolates. Drug sensitivity results for various isolates and their respective clones were comparable at all dosages except for EATRO 1886 isolate which was found to be resistant to 2.5mg/kg of Suramin.
Proceedings of the National Academy of Sciences, 1983
DL-alpha-Difluoromethylornithine, a polyamine biosynthesis inhibitor, and bleomycin, a currently used antineoplastic agent, have each previously been shown to be curative for acute short-term infections of mice with Trypanosoma brucei brucei, an African trypanosome closely related to those that cause the human disease African sleeping sickness. These agents were tested singly and in combination in a previously described mouse model of sleeping sickness with demonstrable brain involvement. The original model is extended by using two additional strains of outbred mice and by demonstrating that melarsoprol, an arsenical and currently the only drug used for human African trypanosomiasis involving the brain, was also curative for these brain infections. Neither difluoromethylornithine nor bleomycin alone was curative for the brain infections; however, many combinations of the two drugs were found to be 100% curative with no evidence of immediate toxicity.
Sahel Journal of Veterinary Sciences, 2020
This study evaluated the efficacy of a combination of artemether and diminazene aceturate therapy in experimental Trypanosoma brucei infection in rats. Thirty five male albino rats used for the study were randomly assigned to seven groups of five rats each as follows: Group A-infected and treated with diminazene aceturate (DA) at 7.0 mg/kg body weight (bw), intramuscular (IM) once on day 7 post-infection (pi); Group B-infected and treated with artemether (ART) at 3.2 mg/kg bw IM on day 7pi and 1.6 mg/kg bw IM on days 8,9,10 and 11pi; Groups C,D and E,-infected and treated with DA at 7.0 mg/kg bw IM, 3.5 mg/kg bw IM, and 1.75 mg/kg bw IM respectively, once on day 7pi and ART at 3.2 mg/kg bw IM on day 7pi plus 1.6 mg/kg bw on days 8,9,10 and 11pi; Group F-infected, untreated and Group G-uninfected, untreated. Onset of parasitaemia (OP), level of parasitaemia (LOP), clearance of parasites post treatment, mortality post infection, relapse of parasitaemia post clearance, rectal temperature, and body weight, were determined at specified intervals during the 70-day experimental period. Results showed that there were no significant (p > 0.05) variations in the OP and LOP between the infected groups. Trypanosomes were cleared from the blood of rats in group A, C, D, and E after treatment. All the rats in groups B and F were dead by day 14pi. The infection relapsed in groups C and E. It was concluded that a combination of DA (3.5 mg/kg bw once) and ART (3.2 mg/kg bw on day 1 of treatment and 1.6 mg/kg bw for 4 consecutive days) exhibited efficacy comparable to the standard dose of DA at 7 mg/kg in the treatment of trypanosome brucei in rats and could thus possibly constitute an effective treatment regimen to reduce the dose of DA and avoid toxicity.
Veterinary World, 2020
Aim: Trypanosomosis is a vital protozoan disease of man and animals with devastating consequences in the tropical parts of the world, necessitating the investigation of the effects of diminazene aceturate (DA) and arteether (AR) on Trypanosoma brucei brucei experimental infection in rats. Materials and Methods: We used a total of 98 rats, which were divided into 14 groups (A-N) of seven rats each over 36 days after acclimatizing them. We administered 1×10 6 trypanosomes to the infected groups (B-N) with Group A as the unexposed control rats. Groups C-F became the infected and treated rats with 3.5 mg/kg, 7.0 mg/kg, 10.5 mg/kg, and 14.0 mg/kg of DA while Groups G-J became the infected and treated rats with 0.01 ml/kg, 0.02 ml/kg, 0.03 ml/kg, and 0.04 ml/kg of AR. Groups K-N became infected and treated rats with DA and AR combinations at similar doses. Results: Parasitemia suppression occurred in Groups G-J only but became cleared in Groups C-F and K-N. Survival time varied significantly (p<0.05) between Group B and the other infected groups. We recorded anemia in all the infected rats while significant (p<0.05) splenomegaly and hepatomegaly occurred in Groups G-J only compared to the other groups. Conclusion: AR did not inhibit or potentiate the anti-trypanosomal efficacy of DA, and therefore, it is comparatively less effective in combating T. brucei infection at the present doses and treatment regimen.
Evaluation of trypanocidal drugs used for human African trypanosomosis against Trypanosoma lewisi
Parasite, 2013
Trypanosomes from animals are potential pathogens for humans. Several human cases infected by Trypanosoma lewisi, a parasite of rats, have been reported. The number of these infections is possibly underestimated. Some infections were self-cured, others required treatment with drugs used in human African trypanosomosis. An in vitro evaluation of these drugs and fexinidazole, a new oral drug candidate, has been performed against T. lewisi in comparison with T. brucei gambiense. All have comparable activities against the two parasites. Suramin was not effective. In vivo, drugs were tested in rats immunosuppressed by cyclophosphamide. The best efficacy was obtained for fexinidazole, and pentamidine (15 mg/kg): rats were cured in 7 and 10 days respectively. Rats receiving nifurtimoxeflornithine combination therapy (NECT) or pentamidine (4 mg/kg) were cured after 28 days, while melarsoprol was weakly active. The identification of efficient drugs with reduced toxicity will help in the management of new cases of atypical trypanosomosis.
Comparative Clinical Pathology, 2016
Trypanosomosis is a disease of both domestic animals and man. Trypanosomosis continues to be a menace in the livestock industry in Nigeria despite the agelong attempt to control the disease. The comparative effects of graded doses of diaminazine aceturate (DA) and fixed doses of iron dextran and vitamin B complex were experimentally investigated in the treatment of Trypanosoma brucei brucei-infected albino mice. A total of 40 albino mice were used and were randomly divided into eight groups of five mice each. All the mice in all the groups except group H were infected with T. brucei brucei, but group H served as the negative control. Groups A and B were treated with graded doses of DA at 3.5 and 7 mg/kg body weight (bw), respectively, groups C, D, E and F were treated as follows: 3.5 mg/kg bw DA and 1 ml/10 kg bw iron dextran, 7.0 mg/kg bw DA plus 1 ml/10 kg bw iron dextran, 3.5 mg/kg bw DA, 1 ml/10 kg bw iron dextran and 1 ml/ 10 kg bw vitamin B complex and 7.0 mg/kg bw DA, 1 ml/ 10 kg bw iron dextran and 1 ml/10 kg bw vitamin B complex, respectively. Group G served as the infected untreated control. Parameters used to assess the effect of the drugs include rectal temperature, body weight changes, packed cell volumes, haemoglobin concentration, daily parasitaemia, clinical signs and survivability. By day 5 PI, all the infected mice had become parasitaemic but following treatment on day 7 PI, the parasites cleared from the blood of the mice in group B and D within 42 hours, groups A, C, E and F before 96 h. There was a significant reduction (P < 0.05) in the mean body weight, packed cell volume and haemoglobin concentration and an increase in rectal temperature following infection but these were reversed by the various treatments. Iron dextran and vitamin B complex were combined with DA, there were improvement in their values, suggesting that combining trypanosomosis therapy with iron dextran and vitamin B complex will help in restoring the physiology of the animal.
Philippine Journal of Veterinary and Animal Sciences, 2012
The development of resistance in trypanosomes to commonly-used trypanocides has an important implication in the chemotherapy and prophylaxis of both human and animal trypanosomosis. This study compared the prophylactic activity of pentamidine isethionate and isometamidium chloride in mice experimentally-infected with Trypanosoma brucei brucei. The 96 mice were divided into four groups with 24 animals each: a) Group Iuntreated control group; b) Group II-treated with pentamidine isethionate at 4 mg/kg body weight for 3 alternate days; c) Group III-treated with pentamidine isethionate at 8 mg/kg body weight for 3 alternate days; and d) Group IV-treated once with isometamidium chloride at 1 mg/kg body weight. Thereafter, three mice from each group were infected intraperitoneally with T. brucei brucei at weekly intervals and monitored for parasitaemia. The entire control group was positive for T. brucei brucei by day 6 post infection. Parasitaemia was recorded in Group II at 3 weeks post infection, at 4 weeks in Group III and at 8 weeks in Group IV. Group IV had the highest survival rate followed by Group III. The results showed that isometamidium chloride provides better prophylaxis than pentamidine isethionate.